{High|Higher} temperature requirement A (HtrA) serine proteases have emerged as a novel class of antibacterial target, {which are|that are} {crucial|essential|vital|critical|important} in protein {quality|high quality|top quality|good quality|excellent|high-quality} {control|manage|handle} and are involved {in the|within the|inside the} pathogenesis of a wide array of bacterial infections. Previously, we demonstrated that HtrA in Chlamydia {is essential|is crucial} for bacterial survival, replication and virulence. {Here|Right here}, we report {a new|a brand new} series of proline (P2)-modified inhibitors of Chlamydia trachomatis HtrA (CtHtrA) {developed|created} by proline ring expansion and Cγ-substitutions. The structure-based drug optimization {process|procedure|method|approach|course of action} was guided by molecular modelling and in vitro pharmacological evaluation of inhibitory potency, selectivity and cytotoxicity. Compound 25 {from the|in the} first-generation 4-substituted proline analogues {increased|elevated|improved|enhanced} antiCtHtrA potency and selectivity {over|more than} human neutrophil elastase (HNE) by {approximately|roughly|around|about} 6- and 12-fold, respectively, relative {to the|towards the|for the} peptidic lead compound 1. {Based on|According to|Depending on|Determined by} this compound, second-generation substituted proline residues containing 1,{2|two},3-triazole moieties {were|had been|have been} synthesized by regioselective azide-alkyne click chemistry. Compound 49 demonstrated {significantly|considerably|substantially|drastically} {improved|enhanced} antichlamydial activity in {whole|entire|complete} cell assays, diminishing the bacterial infectious progeny {below|beneath|under} the detection limit {at the|in the} lowest dose tested. Compound 49 resulted in {approximately|roughly|around|about} 9- and 22-fold improvement {in the|within the|inside the} inhibitory potency and selectivity relative to 1, respectively. To date, compound 49 {is the|will be the|may be the|would be the|could be the|is definitely the} most potent HtrA inhibitor {developed|created} against Chlamydia spp. 4-Nitrobenzenethiol site 3,3′-Oxybis(propan-1-ol) site PMID:36717102
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